Kisumu district, the capital city of Nyanza Province in western Kenya, with a population of 500,000 residents. Most residents self-identify as Luo, an ethnic group that does not traditionally practice circumcision. About 10% of Luo adult men in Kisumu are circumcised. In 2003, HIV prevalence was about 25% in Luo women and 18% in Luo men. The study took place between February 2002 and December 2006.

Participants

Participants were recruited via local newspapers, radio, fliers, and street shows by drama and musical groups. The inclusion criteria were being uncircumcised, HIV-negative, sexually active, aged 18-24 years, resident of Kisumu district with no plans to move for at least two years, hemoglobin of 90 g/L or more, and consent to participate. Exclusion criteria were a foreskin covering less than half the glans, hemophilia or other bleeding disorder, high prothrombin time index, other medical condition contraindicating surgery, and absolute indication for circumcision. Of 6,686 men who were initially screened, 4,489 were eligible for randomization. A total of 1,705 men were excluded due to indecision, lost to follow-up, declined participation, demonstrated insufficient understanding of the protocol, or had the desire for circumcision only, leaving 2,784 for randomization (1,391 in the intervention group and 1,393 in the control group). The median age of randomized participants was 20 years; 98% self-identified as Luo. Two-thirds had greater than a primary education and 64% were unemployed. Seven percent reported being married or living with a partner, and in the previous six months, 14% had no sexual partners, 44% had one partner, and 42% had two or more partners. The treatment groups were much the same in baseline characteristics.

Intervention

Participants were randomly assigned to either the intervention group (circumcision) or the control group (delayed circumcision). Randomly permuted blocks of size 10 and 20 within age group of 18-20 years and 21-24 years were used to ensure approximately equal sample sizes in the two study groups within age strata. Men assigned to the circumcision group were scheduled for surgery the same day or shortly thereafter. Those assigned to the control group were asked to remain uncircumcised until the end of their 24 months of study participation. Surgery was done under local anesthesia in the study clinic by study clinicians using the standardized forceps-guided method. Participants were counseled to refrain from sexual activity for at least 30 days after the procedure, and post-operative checks were performed at 3, 8 and 30 days. All participants received free medical treatment, including sexually transmitted infection treatment, risk-reduction counseling, and condoms during the 24-month follow-up period.

Primary Outcomes

HIV incidence was determined by two different rapid tests. If the results were double positive or discordant, serum was drawn and sent for testing using double ELISA. Participants were deemed to be confirmed positive if the ELISA tests were both positive. If the ELISA tests were discordant, the participants were retested 1-6 months later. Line immunoassay and, if indeterminate, PCR were used to confirm any positive rapid or ELISA test results. Baseline sero-status was verified for all participants confirmed as positive at a follow-up visit. At months 6, 12, 18, and 24, blood and urine were collected for diagnostic testing, and an extensive questionnaire was administered to assess sexual function and behavioral factors associated with HIV infection.

Results

A total of 96% of men in the intervention group were circumcised, and overall follow-up for HIV status was incomplete for 8.6% of participants. The trial was stopped early on December 12, 2006 after a third interim analysis by the data and safety monitoring board. Using intention-to-treat analysis, two-year HIV incidence was 2.1% (95% CI 1.2-3.0) in the circumcision group and 4.2% (95% CI 3.0-5.4) in the control group (p=0.0065). The relative risk of HIV infection in circumcised men was 0.47 (95% CI 0.28-0.78). The Kaplan-Meier estimates of HIV incidence at 12 months were 1.0% (0.5-1.6) for the circumcision group and 2.3% (1.5-3.1%) for the control group (p=0.0103). Adjusting for non-adherence to treatment and excluding four men found to be sero-positive at enrollment, the protective effect of circumcision was 60% (95% CI 32-77). Adverse events to the intervention (21 events in 1.5% of those circumcised) were all mild or moderate in severity and resolved quickly with treatment. There was little difference between circumcised and uncircumcised men in change in sexual behavior measures across the follow-up visits, with the exception of two or more partners in the previous six months (p=0.0383). When comparing baseline and 24 months, fewer men in the control group had unprotected sex (p=0.0349) and more had consistent condom use (p=0.0326).

Conclusions

The authors concluded that male circumcision significantly reduces the risk of HIV acquisition in young men.

Quality Rating

The study was of high quality, according to the Jadad grading system for randomized clinical trials. The study authors pointed out some limitations of the study. Medical workers could not be blinded to treatment; however, non-medical staff who conducted HIV tests, administered questionnaires, and counseled participants about risk reduction were blinded to treatment, although some participants divulged their circumcision status. Measurement of behavioral risk compensation relied on self-report, which could be under- or over-reported. HIV test results were incomplete for 8.6% of the participants; however, there were no baseline differences between those with and without complete follow-up for HIV status. Generalizability of study results to other populations could be limited.

In Context

These findings confirm those from the Orange Farm trial in South Africa (60% [95% CI 32-76] protection against HIV infection in an intention-to-treat analysis and 76% [56-86] in a per-protocol analysis),(1) and those from the Rakai, Uganda trial (51% protective effect).(2) They are also consistent with reductions in HIV prevalence found in a recent meta-analysis of observational studies.(3) Such consistency of clinical, observational, and biological data has not been reported for any other intervention that addresses reduction of HIV incidence in adults. Recent simulation models based on a 60% protective effect and 100% male circumcision estimate that as many as 2 million new HIV infections and 300,000 deaths could be averted over the next ten years in sub-Saharan Africa.(4) The evidence regarding whether circumcised men engage in higher risk behavior than uncircumcised men is mixed--some observational studies have found this to be the case,(5,6) whereas a cohort study summarized in a previous issue of this literature digest did not.(7) Finally, a study in Gauteng Province, South Africa found that male circumcision would be highly cost-effective in that setting, saving about $2.4 million over 20 years per 1,000 circumcisions.(8)

Programmatic Implications

Male circumcision is a highly effective HIV prevention intervention in clinical trial settings where transmission is predominantly heterosexual, and initial research indicates that it is highly cost-effective. Circumcision in younger males prior to sexual activity may increase efficacy. The potential for increased risk behavior in circumcised men, however, is a concern, and must be monitored closely as protective effects of male circumcision become more widely known. Other potential concerns for generalized implementation of male circumcision include the quality of surgical conditions and follow-up, HIV transmission during the post-operative healing period, access to counseling and medical services, and cultural incompatibility where circumcision is currently uncommon. Additionally, this trial was stopped early and long-term outcomes may differ. In summary, voluntary, safe, and affordable circumcision should be integrated with other HIV preventive interventions where appropriate. Additional research is needed to confirm that the intervention is as safe and effective in real-world settings.